Project Summary/Abstract: There is growing consensus that hyperglycemia, as measured by hemoglobin A1c (HbA1c), predicts macrovascular outcomes in addition to microvascular disease in the setting of diabetes. Conventional wisdom in non-diabetic individuals is that HbA1c is important only insofar as it predicts diabetes. Nonetheless, there is accumulating evidence that HbA1c levels within the normal range are associated with clinical outcomes independent of the development of diabetes. We hypothesize that HbA1c is a valuable risk predictor in non- diabetic individuals of not only the onset of diabetes, but also the development of clinical outcomes including cardiovascular disease, kidney disease, retinal disease, and cancer, independent of the subsequent development of diabetes. The specific aims of this project are: (1) to determine the association between HbA1c and progression to diabetes mellitus to accomplish this, we will employ novel statistical techniques to evaluate thresholds for screening of diabetes using HbA1c and fasting glucose alone and in combination; (2) to determine the association of HbA1c with microvascular and macrovascular outcomes in persons without diabetes and to assess whether any associations are explained by the subsequent development of diabetes; and (3) to investigate racial/ethnic disparities in the association of HbA1c with the progression to diabetes and disparities in glucose control among persons with diagnosed diabetes. To achieve these aims, we will measure HbA1c from stored whole blood samples in a large, prospective cohort of non-diabetic individuals from the Atherosclerosis Risk in Communities (ARIC) Study. This project will investigate the clinical relevance of normal and pre-diabetic HbA1c values to shed light on the question: Should we be concerned about high normal HbA1c values in individuals without diabetes? If our hypotheses are correct and HbA1c is shown to be an important risk predictor in adults without diabetes, these results will provoke debate regarding the use of HbA1c as a measure of risk among individuals without a diagnosis of diabetes. Such results would set the stage for clinical trials and intervention studies to investigate the efficacy of lowering glucose levels among individuals with pre-diabetes (e.g., via diet, lifestyle, or even pharmacotherapy). Our results will have direct relevance to clinical practice and should inform strategies for the identification of high-risk individuals and the prevention of diabetes and its complications. Narrative [unreadable] [unreadable] This project will examine the importance of Hemoglobin A1c (HbA1c) in predicting diabetes and other important clinical outcomes (including cardiovascular disease, eye disease, kidney disease, cancer, and heart failure) prior to the onset of diabetes. This research will provide important information regarding the use of HbA1c as a screening test for diabetes and the clinical relevance of HbA1c levels in persons prior to a diagnosis of diabetes. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]